1. Dopamine Function and Reward Processing in Schizophrenia (SZ): We examined brain activity related to reinforcement processing in SZ and its possible relationship to clinical symptoms. Our findings indicate that SZ patients show relatively intact responses to worse-than-expected outcomes in the striatum, but a reduced ability to suppress default network activity and activate areas of frontal cortex, involved in action selection, following salient events. Our current work focuses on neural representations of the value of stimuli and actions in PFC, and their possible contributions to decision-making abnormalities in SZ. 2. Nicotine enhances but does not normalize visual sustained attention in SZ: Understanding the neural basis of how nicotine can transiently improve sustained attention in SZ patients may lead to new treatment strategies. Using the RVIP task, patients had impaired visual sustained attention accuracy and processing speed and showed significantly reduced activation in the frontal-parietal-cingulate-thalamic attention network compared with controls. Nicotine enhanced accuracy and processing speed compared with placebo, with no drug diagnosis interactions. However, patients'task performance remained impaired with nicotine patch, even when compared with controls on placebo. Nicotine exerted no significant reversal of the impaired attention network associated with SZ. Nicotine transiently enhanced sustained attention similarly in both groups. The neural mechanisms for this nicotinic effect in SZ appear similar to those for controls. However, nicotine, at least in a single sustained dose, does not normalize impaired sustained attention and its associated brain network in SZ. 3. Nicotine effects on neurophysiological functions in eye movement and attention in SZ: Behavioral performance and fMRI activation were compared in patients and healthy controls in a double blind, placebo controlled fMRI study to identify the brain regions involved in nicotine-induced change during eye tracking, anticipatory learning of eye movement, sustained attention, and resting state functional connectivity. We are currently examining whether the circuit identified last year that is related to nicotine addiction (Hong et al Arch Gen Psych 2009) can be used as a biomarker to predict changes in smoking behavior. 4. Neurobiological Phenotypes in SZ: Since individuals with SZ have a higher rate of smoking than those in the general population, we hypothesized that genes associated with smoking may be overrepresented in SZ and thus help explain their increased smoking incidence. We tested whether the functional smoking-related nicotinic acetylcholine receptor &#945;5 subunit gene (CHRNA5) nonsynonymous single nucleotide polymorphism (SNP) rs16969968 (Asp398Asn) contributes to smoking in SZ in patients and controls. The Asp398Asn risk allele is significantly associated with smoking severity independently in SZ smokers and control smokers. Furthermore, the same risk allele is significantly associated with SZ in both Caucasian and African-American nonsmoker SZ patients compared with control nonsmokers. Intriguingly, this SNP was not significantly associated with smoking status (smokers vs. nonsmokers) in either SZ patients or controls. Therefore, our study identifies a genetic variant that is simultaneously linked to smoking and SZ in the same cohort, but whether this SNP contributes to the increased smoking prevalence in SZ patients requires additional studies. 5. Effects of smoking and SZ on white matter abnormalities: Whole brain white matter integrity (fractional anisotropy (FA)) was measured in patients and healthy control subjects. Smoking status and SZ were independently and additively associated with reduced FA in left anterior thalamic radiation/anterior limb of the internal capsule, and significant FA decreases were identified in the bilateral uncinate fasciculus/inferior fronto-occipital fasciculus in SZ and the left prefrontal area in smoking status separately. Common and distinct patterns of impaired white matter are associated with SZ and smoking. Particularly, the anatomic congruence of an additive white matter abnormality in the anterior thalamic radiation/anterior limb of the internal capsule suggests that this abnormal fiber connection between frontal cortex and striatum/thalamus may be a biomarker for the increased comorbid smoking in SZ patients. 6. Insula and Anterior Cingulate Resting State Functional Connectivity in SZ Smokers: The cause of the high rate of smoking in SZ patients remains unclear. We previously found that a dorsal anterior cingulate (dACC) striatum resting state functional connectivity (rsFC) circuit is associated with nicotine addiction in normal controls and patients. The insula is closely related to smoking and the ability to quit. Therefore, we hypothesized that SZ smokers may have more dysfunction in smoking-related insular and dACC circuits compared with control smokers, thus explaining their higher propensity to smoke. Using individually identified anterior and posterior insula, and dACC as seed regions, rsFC with the rest of the brain was determined. Significant decreases in rsFC that correlated with increased smoking severity were found in circuits between insula, dACC and striatum in both SZ and normal control smokers. These significant relationships between nicotine addiction severity and rsFC were similar between the two groups. Furthermore, subjects with SZ had additional decreases in rsFC in circuits between the dACC and insula. Reduced rsFC between the insula, dACC and striatum may underlie nicotine dependence in non-psychiatrically ill subjects as well as in SZ patients. Decreased rsFC between the dACC and insula may index an overlapping functional circuitry associated with smoking and SZ and may be a circuit biomarker for the increased smoking in SZ. 7. Effects of Prenatal Drug Exposure (PDE) on Adolescent Brain Functioning: The goal is to examine the consequences of exposure to drugs in utero in adolescents to the neurobiological mechanisms of risky decision making, working memory and functional connectivity. New findings indicate that while there is no behavioral difference between PDE and healthy adolescents on risky decision making, PDE adolescents demonstrate widespread increased activation in areas including cingulate, insula, inferior frontal gyrus, posterior temporal, parietal and occipital regions. Network circuit analysis using graph theory to examine working memory processes indicates reduced global and local efficiency in PDE adolescents. Finally, volumetric analyses indicate PDE adolescents have greater hippocampal volume that correlates negatively with measures of memory function.